title: Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.
abstract: Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, in rodents has been proposed as a useful experimental model of HD. This study evaluated the effects of probucol, a lipid-lowering agent with anti-inflammatory and antioxidant properties, on the biochemical parameters related to oxidative stress, as well as on the behavioral parameters related to motor function in an in vivo HD model based on 3-NP intoxication in rats. Animals were treated with 3.5 mg/kg of probucol in drinking water daily for 2 months and, subsequently, received 3-NP (25 mg/kg i.p.) once a day for 6 days. At the end of the treatments, 3-NP-treated animals showed a significant decrease in body weight, which corresponded with impairment on motor ability, inhibition of mitochondrial complex II activity and oxidative stress in the striatum. Probucol, which did not rescue complex II inhibition, protected against behavioral and striatal biochemical changes induced by 3-NP, attenuating 3-NP-induced motor impairments and striatal oxidative stress. Importantly, probucol was able to increase activity of glutathione peroxidase (GPx), an enzyme important in mediating the detoxification of peroxides in the central nervous system. The major finding of this study was that probucol protected against 3-NP-induced behavioral and striatal biochemical changes without affecting 3-NP-induced mitochondrial complex II inhibition, indicating that long-term probucol treatment resulted in an increased resistance against neurotoxic events (i.e., increased oxidative damage) secondary to mitochondrial dysfunction. These data appeared to be of great relevance when extrapolated to human neurodegenerative processes involving mitochondrial dysfunction and indicates that GPx is an important molecular target involved in the beneficial effects of probucol.
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil. dirleise@yahoo.com.br
authors.forename: Dirleise
authors.initials: D
authors.lastname: Colle
authors.forename: Danúbia Bonfanti
authors.initials: DB
authors.lastname: Santos
authors.forename: Eduardo Luiz Gasnhar
authors.initials: EL
authors.lastname: Moreira
authors.forename: Juliana Montagna
authors.initials: JM
authors.lastname: Hartwig
authors.forename: Alessandra Antunes
authors.initials: AA
authors.lastname: dos Santos
authors.forename: Luciana Teixeira
authors.initials: LT
authors.lastname: Zimmermann
authors.forename: Mariana Appel
authors.initials: MA
authors.lastname: Hort
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002374:Catalase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D004353:Drug Evaluation, Preclinical; D042963:Electron Transport Complex II / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D015227:Lipid Peroxidation; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009574:Nitro Compounds; D018384:Oxidative Stress; D011341:Probucol / Q000494:pharmacology* / Q000627:therapeutic use; D011422:Propionates; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D013482:Superoxide Dismutase / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000975:Antioxidants; D009574:Nitro Compounds; D011422:Propionates; D002374:Catalase; D005979:Glutathione Peroxidase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase; D042963:Electron Transport Complex II; D005980:Glutathione Reductase; D011341:Probucol; C015392:3-nitropropionic acid